Prolongation of cardiac repolarization (increased QT duration) is linked to provocation of serious ventricular arrhythmias in some settings, but to arrhythmia suppression in others. Up to 11% of patients started on quinidine develop marked increases in QT and potentially fatal polymorphic ventricular tachycardia ("Torsades de Pointes"). On the other hand, marked QT increases are an invariable accompaniment of arrhythmia suppression by amiodarone, which only very rarely causes Torsades de Pointes. The research proposed will test the hypothesis that a specific in vitro electrophysiologic abnormality, bradycardia-dependent early afterdepolarization (EADs), triggers Torsades de Pointes in vivo. This hypothesis has its foundation in a series of clinical and laboratory studies we have conducted on quinidine-induced prolonged repolarization. In patients, we found that the occurrence of Torsades de Pointes was associated with a high incidence of hypokalemia and invariably started after an abrupt increase in cycle length. In canine Purkinje fibers superfused with low concentrations of quinidine, lowering potassium during slow stimulation consistently triggered EADs. Furthermore, interventions abolishing EADs (increasing potassium or stimulation rate) were the same as those which are most effective in Torsades de Pointes. The hypothesized role of EADs in triggering Torsades de Pointes will be further explored in three ways in this proposal. First, agents thought to cause Torsades de Pointes (disopyramide, procainamide, quinidine metabolites) will be tested in canine Purkinje fibers for their ability to induce EADs; interventions which prolong action potential but do not induce this arrhythmia (amiodarone, hypocalcemia) will be similarly evaluated. Second, ventricular monophasic action potentials will be recorded in an animal model of Torsades de Pointes, hypokalemic dogs with slow heart rates (AV block) treated with quinidine or other agents reported to induce EADs in vitro (N-acetylprocainamide, cesium). We have observed abnormalities in monophasic action potentials in such animals which we believe to represent EADs. The relationship of such abnormalities to previous cycle length, Torsades de Pointes onset, and drugs which prevent Torsades de Pointes will be evaluated to confirm this finding, thereby strengthening the link between the in vitro and in vivo abnormalities. Third, monophasic action potential will be recorded in patients receiving action potential prolonging drugs and in patients with previous Torsades de Pointes. In this way, methods to identify patients at risk for Torsades de Pointes will be improved. This research will identify circumstances under which prolongation of cardiac repolarization induces arrhythmias, thereby providing the basis for improved antiarrhythmic drug therapy.